TY - JOUR
T1 - Functional Characterization of Six SLCO1B1 (OATP1B1) Variants Observed in Finnish Individuals with a Psychotic Disorder
AU - Häkkinen, Katja
AU - Kiander, Wilma
AU - Kidron, Heidi
AU - Lähteenvuo, Markku
AU - Urpa, Lea
AU - Lintunen, Jonne
AU - Vellonen, Kati Sisko
AU - Auriola, Seppo
AU - Holm, Minna
AU - Lahdensuo, Kaisla
AU - Kampman, Olli
AU - Isometsä, Erkki
AU - Kieseppä, Tuula
AU - Lönnqvist, Jouko
AU - Suvisaari, Jaana
AU - Hietala, Jarmo
AU - Tiihonen, Jari
AU - Palotie, Aarno
AU - Ahola-Olli, Ari V.
AU - Niemi, Mikko
N1 - Funding Information:
The SUPER-Finland study was funded by The Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, Boston, USA. K.H. has received funding from The Ministry of Social Affairs and Health Finland through the developmental fund for Niuvanniemi Hospital, Kuopio, Finland, The Finnish Cultural Foundation, Helsinki, Finland, The Finnish Foundation for Psychiatric Research, Helsinki, Finland, The Social Insurance Institution of Finland, Helsinki, Finland, The Emil Aaltonen Foundation, Tampere, Finland, The Academy of Finland, Helsinki, Finland, and The Yrjö Jahnsson Foundation (20207277), Helsinki, Finland. W.K. was funded by The Finnish Cultural Foundation, Helsinki, Finland, and The Academy of Finland (332949), Helsinki, Finland. M.L. has received funding from The Finnish Medical Foundation, Helsinki, Finland, and The Emil Aaltonen Foundation, Tampere, Finland. J.L. has received funding from The Finnish Medical Foundation, Helsinki, Finland, and The Finnish Foundation for Psychiatric Research, Helsinki, Finland. M.H. has received funding from The Academy of Finland (310295), Helsinki, Finland. A.V.A. has received funding from The Orion Research Foundation, Espoo, Finland, The Juho Vainio Foundation, Helsinki, Finland, and The Finnish Post Doc Pool. M.N. was funded by The European Research Council Consolidator Grant (grant agreement ID: 725249). The School of Pharmacy mass spectrometry laboratory in Kuopio is supported by Biocenter Kuopio and Biocenter Finland.
Funding Information:
We thank the SUPER-Finland study participants. We would like to thank the collaborating SUPER-Finland study group: Mark Daly, Steve Hyman, Amanda Elliott, Benjamin Neale, Willehard Haaki, Teemu Männynsalo, Tuomas Jukuri, Kimmo Suokas, Jussi Niemi-Pynttäri, Asko Wegelius, Risto Kajanne, Aija Kyttälä, Noora Ristiluoma, Hannu Turunen, Auli Toivola, Annamari Tuulio-Henriksson, Tiina Paunio, Juha Veijola, Katriina Hakakari, Elina Hietala, Jaakko Keinänen, Martta Kerkelä, Tuomo Kiiskinen, Sari Lång-Tonteri, Nina Lindberg, Ville Mäkipelto, Atiqul Mazumder, Erik Cederlöf, Zuzanna Misiewicz, Julia Moghadampour, Arto Mustonen, Solja Niemelä, Olli Pietiläinen, Susanna Rask, Elmo Saarentaus, Anssi Solismaa, Andre Sourander, Marjo Taivalantti, and Imre Västrik for the SUPER study data and support. We would like to thank Marju Monnonen, Natalija Trunkelj, Noora Sjöstedt, and Laura Suominen for technical assistance as well as Dr. Yasuo Uchida for consultation on sample preparation of the proteomics samples. Dr. Mikko Gynther is acknowledged for the methodology in proteomics. We thank Mikko Neuvonen for rosuvastatin quantification. We acknowledge the Drug Discovery and Chemical Biology Network for providing access to screening instrumentation and the Genomics Platform of the Broad Institute of MIT and Harvard for whole exome sequencing of the SUPER-Finland study samples. The SUPER-Finland study was funded by The Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, Boston, USA. K.H. has received funding from The Ministry of Social Affairs and Health Finland through the developmental fund for Niuvanniemi Hospital, Kuopio, Finland, The Finnish Cultural Foundation, Helsinki, Finland, The Finnish Foundation for Psychiatric Research, Helsinki, Finland, The Social Insurance Institution of Finland, Helsinki, Finland, The Emil Aaltonen Foundation, Tampere, Finland, The Academy of Finland, Helsinki, Finland, and The Yrjö Jahnsson Foundation (20207277), Helsinki, Finland. W.K. was funded by The Finnish Cultural Foundation, Helsinki, Finland, and The Academy of Finland (332949), Helsinki, Finland. M.L. has received funding from The Finnish Medical Foundation, Helsinki, Finland, and The Emil Aaltonen Foundation, Tampere, Finland. J.L. has received funding from The Finnish Medical Foundation, Helsinki, Finland, and The Finnish Foundation for Psychiatric Research, Helsinki, Finland. M.H. has received funding from The Academy of Finland (310295), Helsinki, Finland. A.V.A. has received funding from The Orion Research Foundation, Espoo, Finland, The Juho Vainio Foundation, Helsinki, Finland, and The Finnish Post Doc Pool. M.N. was funded by The European Research Council Consolidator Grant (grant agreement ID: 725249). The School of Pharmacy mass spectrometry laboratory in Kuopio is supported by Biocenter Kuopio and Biocenter Finland.
Funding Information:
The authors declare the following competing financial interest(s): K.H. is an employee of CRO company IQVIA. M.L. is a board member of Genomi Solutions ltd., and Nursie Health ltd. and Springflux ltd., has received honoraria from Sunovion ltd., Orion Pharma ltd., Lundbeck, Otsuka Pharma, Recordati, Janssen and Janssen-Cilag. J.T. has participated in research projects funded by grants from Eli Lilly and Janssen-Cilag to his employing institution, has received honoraria from Eli Lilly, Evidera, Janssen-Cilag, Lundbeck, Otsuka, Mediuutiset, Sidera, and Sunovion, and is consultant to HLS Therapeutics, Orion, and WebMed Global. A.V.A is an employee and shareholder of Abomics, a company providing pharmacogenetic consultation services. The other authors declare no conflict of interest. Acknowledgments
Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society.
PY - 2023
Y1 - 2023
N2 - Variants in the SLCO1B1 (solute carrier organic anion transporter family member 1B1) gene encoding the OATP1B1 (organic anion transporting polypeptide 1B1) protein are associated with altered transporter function that can predispose patients to adverse drug effects with statin treatment. We explored the effect of six rare SLCO1B1 single nucleotide variants (SNVs) occurring in Finnish individuals with a psychotic disorder on expression and functionality of the OATP1B1 protein. The SUPER-Finland study has performed exome sequencing on 9381 individuals with at least one psychotic episode during their lifetime. SLCO1B1 SNVs were annotated with PHRED-scaled combined annotation-dependent (CADD) scores and the Ensembl variant effect predictor. In vitro functionality studies were conducted for the SNVs with a PHRED-scaled CADD score of >10 and predicted to be missense. To estimate possible changes in transport activity caused by the variants, transport of 2′,7′-dichlorofluorescein (DCF) in OATP1B1-expressing HEK293 cells was measured. According to the findings, additional tests with rosuvastatin and estrone sulfate were conducted. The amount of OATP1B1 in crude membrane fractions was quantified using a liquid chromatography tandem mass spectrometry-based quantitative targeted absolute proteomics analysis. Six rare missense variants of SLCO1B1 were identified in the study population, located in transmembrane helix 3: c.317T>C (p.106I>T), intracellular loop 2: c.629G>T (p.210G>V), c.633A>G (p.211I>M), c.639T>A (p.213N>L), transmembrane helix 6: 820A>G (p.274I>V), and the C-terminal end: 2005A>C (p.669N>H). Of these variants, SLCO1B1 c.629G>T (p.210G>V) resulted in the loss of in vitro function, abolishing the uptake of DCF, estrone sulfate, and rosuvastatin and reducing the membrane protein expression to 31% of reference OATP1B1. Of the six rare missense variants, SLCO1B1 c.629G>T (p.210G>V) causes a loss of function of OATP1B1 transport in vitro and severely decreases membrane protein abundance. Carriers of SLCO1B1 c.629G>T might be susceptible to altered pharmacokinetics of OATP1B1 substrate drugs and might have increased likelihood of adverse drug effects such as statin-associated musculoskeletal symptoms.
AB - Variants in the SLCO1B1 (solute carrier organic anion transporter family member 1B1) gene encoding the OATP1B1 (organic anion transporting polypeptide 1B1) protein are associated with altered transporter function that can predispose patients to adverse drug effects with statin treatment. We explored the effect of six rare SLCO1B1 single nucleotide variants (SNVs) occurring in Finnish individuals with a psychotic disorder on expression and functionality of the OATP1B1 protein. The SUPER-Finland study has performed exome sequencing on 9381 individuals with at least one psychotic episode during their lifetime. SLCO1B1 SNVs were annotated with PHRED-scaled combined annotation-dependent (CADD) scores and the Ensembl variant effect predictor. In vitro functionality studies were conducted for the SNVs with a PHRED-scaled CADD score of >10 and predicted to be missense. To estimate possible changes in transport activity caused by the variants, transport of 2′,7′-dichlorofluorescein (DCF) in OATP1B1-expressing HEK293 cells was measured. According to the findings, additional tests with rosuvastatin and estrone sulfate were conducted. The amount of OATP1B1 in crude membrane fractions was quantified using a liquid chromatography tandem mass spectrometry-based quantitative targeted absolute proteomics analysis. Six rare missense variants of SLCO1B1 were identified in the study population, located in transmembrane helix 3: c.317T>C (p.106I>T), intracellular loop 2: c.629G>T (p.210G>V), c.633A>G (p.211I>M), c.639T>A (p.213N>L), transmembrane helix 6: 820A>G (p.274I>V), and the C-terminal end: 2005A>C (p.669N>H). Of these variants, SLCO1B1 c.629G>T (p.210G>V) resulted in the loss of in vitro function, abolishing the uptake of DCF, estrone sulfate, and rosuvastatin and reducing the membrane protein expression to 31% of reference OATP1B1. Of the six rare missense variants, SLCO1B1 c.629G>T (p.210G>V) causes a loss of function of OATP1B1 transport in vitro and severely decreases membrane protein abundance. Carriers of SLCO1B1 c.629G>T might be susceptible to altered pharmacokinetics of OATP1B1 substrate drugs and might have increased likelihood of adverse drug effects such as statin-associated musculoskeletal symptoms.
KW - drug transporter
KW - OATP1B1
KW - organic anion transporting polypeptide 1B1
KW - pharmacogenetics
KW - SLCO1B1
U2 - 10.1021/acs.molpharmaceut.2c00715
DO - 10.1021/acs.molpharmaceut.2c00715
M3 - Article
C2 - 36779498
AN - SCOPUS:85148280477
SN - 1543-8384
VL - 20
SP - 1500
EP - 1508
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
IS - 3
ER -